Submissions for variant NM_024422.6(DSC2):c.835C>T (p.Arg279Cys)

gnomAD frequency: 0.00005  dbSNP: rs193922708

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488350	SCV000052317	likely benign	not specified	2023-12-28	criteria provided, single submitter	clinical testing	Variant summary: DSC2 c.835C>T (p.Arg279Cys) results in a non-conservative amino acid change located in the Cadherin-like domain (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251360 control chromosomes. The observed variant frequency is approximately 1.9 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.835C>T has been reported in the literature in cohorts of individuals with arrhythmogenic right ventricular cardiomyopathy (example, Alcade_2014) and left ventricular noncompaction cardiomyopathy (LVNC) (example, Li_2019). These report(s) do not provide unequivocal conclusions about association of the variant with DSC2-related Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. At-least two co-occurrences with other pathogenic variant(s) have been reported in individuals with arrhythmogenic right ventricular cardiomyopathy (PKP2) or left ventricular noncompaction cardiomyopathy (LVNC) (Alcade_2014, PKP2 c.1882delC, p.Gln628Argfs*28; Li_2019, TNNT2 c.305G>A, p.Arg102Gln), providing supporting evidence for a benign role attributed to an alternative molecular basis of disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24832006, 31397097). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was re-classified as likely benign.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171894	SCV000054844	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV001122945	SCV001281729	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000029665	SCV001341208	uncertain significance	Cardiomyopathy	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 279 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy and in another individual affected with left ventricular noncompaction and hypertrophic cardiomyopathy (PMID: 31397097, 32268277). Both of them also carried a pathogenic variant in a different gene that could explain the observed phenotype, suggesting that this DSC2 variant may not have been the cause of cardiomyopathy in these two individuals. This variant has been identified in 12/251360 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae	RCV001122945	SCV002200888	uncertain significance	Arrhythmogenic right ventricular dysplasia 11	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 279 of the DSC2 protein (p.Arg279Cys). This variant is present in population databases (rs193922708, gnomAD 0.01%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy or left ventricular noncompaction with hypertrophic cardiomyopathy (PMID: 24832006, 31397097). ClinVar contains an entry for this variant (Variation ID: 36007). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSC2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Dept of Medical Biology, Uskudar University	RCV003318335	SCV004021956	uncertain significance	Long QT syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PM2
All of Us Research Program, National Institutes of Health	RCV003996118	SCV004816205	uncertain significance	Familial isolated arrhythmogenic right ventricular dysplasia	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 279 of the DSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy and in another individual affected with left ventricular noncompaction and hypertrophic cardiomyopathy (PMID: 31397097, 32268277). Both of them also carried a pathogenic variant in a different gene that could explain the observed phenotype, suggesting that this DSC2 variant may not have been the cause of cardiomyopathy in these two individuals. This variant has been identified in 12/251360 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004018685	SCV005028753	benign	Cardiovascular phenotype	2024-01-23	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.